Cedazuridine + Azacitidine for Leukemia

Recruiting at25 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2 & 3

Recruiting

Sponsor: Astex Pharmaceuticals, Inc.

Must be taking: Azacitidine

Must not be taking: Decitabine, Guadecitabine

Disqualifiers: HIV, Hepatitis B/C, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial tests a new pill form of two drugs, cedazuridine and azacitidine, for patients needing azacitidine treatment. The goal is to see if the pill is as effective as the injection. Cedazuridine helps azacitidine work better by preventing its breakdown, and azacitidine stops cancer cells from growing.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have had cytotoxic chemotherapy (except hydroxyurea) within 4 weeks before starting the study treatment, and you should not be on any investigational drugs or therapies within 2 weeks before the first dose.

What data supports the effectiveness of the drug Azacitidine for leukemia?

Azacitidine has been shown to significantly prolong survival in patients with higher-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) compared to conventional care. It also reduces the risk of AML progression and increases rates of complete and partial remission. ^{1 2 3 4 5}

Is the combination of Cedazuridine and Azacitidine safe for humans?

Azacitidine, used in combination with Cedazuridine, has been studied for safety in patients with leukemia and related conditions. Common side effects include low blood cell counts, fatigue, and fever, but serious side effects leading to stopping treatment are rare. With proper management, it is generally considered safe for most patients. ^{1 2 6 7 8}

What makes the drug Cedazuridine + Azacitidine unique for treating leukemia?

The combination of Cedazuridine and Azacitidine is unique because Cedazuridine helps increase the effectiveness of Azacitidine by preventing its breakdown in the body, allowing for oral administration instead of the usual subcutaneous (under the skin) injection, which can be more convenient for patients. ^{1 3 5 9 10}

Research Team

Eligibility Criteria

This trial is for adults with certain blood disorders like MDS, CMML, or AML who can benefit from azacitidine treatment. They should be physically stable (ECOG 0-1), expected to live at least 12 weeks, able to swallow pills and fast for 4 hours. Pregnant women can't join; participants need proper liver and kidney function and no recent major surgeries or chemotherapy.

Inclusion Criteria

I haven't had chemotherapy in the last 4 weeks.

I can swallow several pills within 10 minutes and fast for 4 hours.

My liver function tests are within the required range.

Exclusion Criteria

I have had more than one cycle of specific chemotherapy treatments.

I have MDS/MPN and can feel swelling in my liver or spleen.

I do not have any severe illnesses or conditions that could risk my safety in the study.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1: Dose Escalation

Open-label dose escalation stage using multiple cohorts at escalating dose levels of oral cedazuridine and azacitidine

28 days per cycle

Multiple visits per cycle

Phase 1: Dose Expansion

Dose expansion stage with oral azacitidine followed by SC azacitidine, ASTX030, and oral cedazuridine

28 days per cycle

Multiple visits per cycle

Phase 2: Randomized Crossover

Randomized, open-label crossover study comparing oral ASTX030 to SC azacitidine

28 days per cycle

Multiple visits per cycle

Phase 3: Randomized Crossover

Randomized open-label crossover study comparing the final oral ASTX030 dose to SC azacitidine

28 days per cycle

Multiple visits per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 36 months

Treatment Details

Interventions

• Azacitidine (Anti-metabolites)
• Cedazuridine (Anti-metabolites)

Trial Overview The study tests ASTX030 (oral cedazuridine combined with azacitidine) against subcutaneous azacitidine alone in three phases: dose escalation, dose expansion, then a randomized comparison of the final oral dose versus the injection form over approximately four years.

Participant Groups

Group I: Phase 3, Sequence A & B Experimental Treatment 2 Interventions

In Sequence A: Participants will receive ASTX030 in Cycle 1, followed by SC azacitidine in Cycle 2; all participants will receive ASTX030 in subsequent cycles (Cycles ≥3). In Sequence B: Participants will receive SC azacitidine in Cycle 1 followed by ASTX030 in Cycle 2; all participants will receive ASTX030 in subsequent cycles (Cycles ≥3).

Group II: Phase 2, Part B, Sequence A & B Experimental Treatment 2 Interventions

In Sequence A: Oral ASTX030 (cedazuridine + azacitidine) will be administered in Cycle 1, followed by SC azacitidine in Cycle 2; all participants will receive ASTX030 in subsequent cycles (Cycles ≥3). In Sequence B: SC azacitidine will be administered in Cycle 1, followed by oral cedazuridine + azacitidine tablets/capsules in Cycle 2; all participants will receive ASTX030 in subsequent cycles (Cycles ≥3).

Group III: Phase 1, Stage B (Dose Expansion) Experimental Treatment 3 Interventions

In Cycle 1 (28 days per cycle), single dose oral azacitidine will be administered, followed by SC azacitidine, ASTX030 and oral cedazuridine on a specific dosing schedule; in Cycle 2, oral ASTX030 (cedazuridine + azacitidine) will be administered. On Day 7 of Cycle 2 drug products will administered in a fed state and all other doses will be administered in fasted state.

Group IV: Phase 1, Stage A (Dose Escalation) Experimental Treatment 3 Interventions

In Cycle 1 (28 days per cycle), single dose oral azacitidine will be administered, followed by subcutaneous (SC) azacitidine, ASTX030 and oral cedazuridine on a specific dosing schedule; in Cycle 2, oral ASTX030 (cedazuridine + azacitidine) will be administered.

Azacitidine is already approved in Canada, Japan for the following indications:

Approved in Canada as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

Astex Pharmaceuticals, Inc.

Lead Sponsor

Trials

97

Recruited

7,400+

Dr. Harren Jhoti

Astex Pharmaceuticals, Inc.

Chief Executive Officer since 2007

PhD in Biochemistry from Birkbeck College, London

Dr. Harold N. Keer

Astex Pharmaceuticals, Inc.

Chief Medical Officer since 2020

MD

Taiho Oncology, Inc.

Lead Sponsor

Trials

79

Recruited

12,700+

Tim Whitten

Taiho Oncology, Inc.

Chief Executive Officer since 2018

MBA and Pharmacy degree

Harold Keer

Taiho Oncology, Inc.

Chief Medical Officer

MD, PhD

Findings from Research

The Vidaza Access Program in Belgium successfully facilitated access to azacitidine treatment for 175 patients with myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML) by streamlining the approval process for patient dossiers.

Out of the 175 patient dossiers submitted, 163 were approved by Celgene, demonstrating the program's effectiveness in ensuring timely treatment initiation without financial risk to hospitals, which is crucial for patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine access program for Belgian patients with myelodysplastic syndromes, acute myeloid leukemia or chronic myelomonocytic leukemia. Meers, S., Selleslag, D., Potier, H., et al.[2018]

In a real-life study of 49 patients with myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), and chronic myelomonocytic leukaemia (CMML), azacitidine demonstrated a clinically acceptable safety profile, with 67.3% of patients experiencing treatment-related adverse events.

Efficacy results showed that 41.4% of MDS and CMML patients achieved a complete or partial response, and 43.8% of transfusion-dependent patients became transfusion-independent, with a median overall survival of 490 days.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of azacitidine in Belgian patients with high-risk myelodysplastic syndromes, acute myeloid leukaemia, or chronic myelomonocytic leukaemia: results of a real-life, non-interventional post-marketing survey. Beguin, Y., Selleslag, D., Meers, S., et al.[2015]

Azacitidine (Vidaza) is the only drug approved in the EU that significantly prolongs survival in adults with high-risk myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), making it a crucial treatment option for patients not eligible for stem cell transplantation.

The treatment is associated with a lower risk of AML progression and higher rates of remission and blood transfusion independence, while maintaining an acceptable safety profile, with peripheral cytopenias being the most common side effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine: a review of its use in higher-risk myelodysplastic syndromes/acute myeloid leukaemia. Keating, GM.[2021]

The ROMAZA trial established that the maximum tolerated dose of the combination therapy of romidepsin (ROM) and azacitidine (AZA) for treating acute myeloid leukaemia (AML) is ROM 12 mg/m2 on Days 8 and 15, along with AZA 75 mg/m2 for a 7/28 day cycle.

Out of 38 patients treated at this maximum tolerated dose, 23.7% achieved a response by Cycle 6, with 7 patients reaching complete remission and 2 achieving partial response, indicating the potential efficacy of this combination therapy in AML patients who cannot undergo intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination romidepsin and azacitidine therapy is well tolerated and clinically active in adults with high-risk acute myeloid leukaemia ineligible for intensive chemotherapy. Loke, J., Metzner, M., Boucher, R., et al.[2022]

In a study of 1406 patients receiving azacitidine, the most common severe adverse events were hematologic, with grade 3-4 anemia occurring in 43.4% of patients, which was higher than reported in clinical trials.

Despite the high frequency of adverse events, treatment discontinuation due to these events was low (5.1%), indicating that with proper management, azacitidine can be safely administered to most patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events in 1406 Patients Receiving 13,780 Cycles of Azacitidine within the Austrian Registry of Hypomethylating Agents-A Prospective Cohort Study of the AGMT Study-Group. Leisch, M., Pfeilstöcker, M., Stauder, R., et al.[2022]

Azacitidine (AZA) significantly prolonged overall survival by 3.9 months compared to conventional care regimens in older patients (≥65 years) with acute myeloid leukemia (AML).

Patients treated with AZA experienced lower rates of treatment-emergent adverse events (TEAEs) and related hospitalizations compared to those receiving best supportive care, suggesting that AZA is a safer option for older patients who cannot tolerate intensive therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence rates of treatment-emergent adverse events and related hospitalization are reduced with azacitidine compared with conventional care regimens in older patients with acute myeloid leukemia. Seymour, JF., Döhner, H., Minden, MD., et al.[2019]

5-Azacytidine has shown a 36% overall response rate and 20% complete remission in patients with acute myelogenous leukemia (AML) who have previously been treated, indicating its potential effectiveness in this specific cancer.

While the drug has dose-limiting toxicities such as nausea, vomiting, and leukopenia, it has low incidence of thrombocytopenia and varying degrees of hepatic toxicity, suggesting that its safety profile needs careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

5-Azacytidine. A new anticancer drug with effectiveness in acute myelogenous leukemia. Von Hoff, DD., Slavik, M., Muggia, FM.[2019]

Azacitidine significantly improves response rates and overall survival in patients with myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), with a median survival increase of 9.4 months compared to conventional care in higher-risk patients.

The treatment is generally well tolerated, with peripheral cytopenias being the most common side effect, along with gastrointestinal issues and injection-site reactions, making it a viable option for elderly patients as well.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine: a review of its use in the management of myelodysplastic syndromes/acute myeloid leukaemia. Keating, GM.[2022]

Azacitidine is an effective and well-tolerated treatment for patients with higher-risk myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), including older patients who are ineligible for stem cell transplants, as demonstrated in pivotal phase 3 trials.

It is the only approved hypomethylating agent that has been shown to prolong overall survival compared to conventional care, making it the recommended first-line treatment for most patients with higher-risk MDS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine: A Review in Myelodysplastic Syndromes and Acute Myeloid Leukaemia. Scott, LJ.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Azacitidine access program for Belgian patients with myelodysplastic syndromes, acute myeloid leukemia or chronic myelomonocytic leukemia. [2018]

2. England pubmed.ncbi.nlm.nih.gov

Safety and efficacy of azacitidine in Belgian patients with high-risk myelodysplastic syndromes, acute myeloid leukaemia, or chronic myelomonocytic leukaemia: results of a real-life, non-interventional post-marketing survey. [2015]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Azacitidine: a review of its use in higher-risk myelodysplastic syndromes/acute myeloid leukaemia. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Azacitidine for the treatment of patients with acute myeloid leukemia with 20%-30% blasts and multilineage dysplasia. [2017]

5. England pubmed.ncbi.nlm.nih.gov

Combination romidepsin and azacitidine therapy is well tolerated and clinically active in adults with high-risk acute myeloid leukaemia ineligible for intensive chemotherapy. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Adverse Events in 1406 Patients Receiving 13,780 Cycles of Azacitidine within the Austrian Registry of Hypomethylating Agents-A Prospective Cohort Study of the AGMT Study-Group. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Incidence rates of treatment-emergent adverse events and related hospitalization are reduced with azacitidine compared with conventional care regimens in older patients with acute myeloid leukemia. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

5-Azacytidine. A new anticancer drug with effectiveness in acute myelogenous leukemia. [2019]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Azacitidine: a review of its use in the management of myelodysplastic syndromes/acute myeloid leukaemia. [2022]

10. New Zealand pubmed.ncbi.nlm.nih.gov

Azacitidine: A Review in Myelodysplastic Syndromes and Acute Myeloid Leukaemia. [2022]